The primary objective of this project continues to be the in vivo study of the receptors involved in the actions of morphine and related compounds (including the endogenous opioid peptides and their synthetic analogs). The focus will be on determining the roles played by the receptors and the endogenous ligands in normal homeostasis and in perturbed homeostasis, including opioid tolerance and dependence. Concentration will be on two systems known to be influenced by opioids: temperature regulation and pupillary control, and on two types of opioid receptors: mu and kappa. Other measures such as analgesia, seizure threshold, and EEG changes, as well as other receptors (e.g., delta and sigma) will be studied where appropriate. Whole- animal calorimetry will be used to examine the relationship among body temperature, heat loss, and oxygen consumption on these drug responses. An understanding of the role of opioid receptors in thermoregulatory processes could prove to be of therapeutic value in the "near-drowning" syndrome, hypothermia, and cardiac surgery. Experiments to explore the relationships among pupillary size and fluctuations, intermittent electrographic bursting, site of activation, and respiration will be conducted after acute and chronic drug administration to determine if opioid receptors have a physiological function in pupillary control. Dose-response data on pupillary changes will be collected by means of infrared videopupillography and analyzed by computer. As a possible explanation for the marked qualitative differences observed in temperature, pupil, and seizure threshold responses to centrally vs. peripherally administered drugs, drug distribution following injection by different routes will be studied using autoradiographic, HPLC, and thin-layer chromatographic methods to explore the mechanisms involved. Since no neuroregulatory system operates in isolation in the living organism, investigations into the interactions of opioids with other neuropeptides will be carried out. In addition, in view of the prevalence of polydrug abuse in society, the interactions of opioids with other drugs of abuse such as cocaine and marijuana will be examined. The ultimate goal of these studies is to understand the function of opioid receptors and their ligands in the body and how tolerance, dependence, and other drugs of abuse alter those functions. Such knowledge can be expected to aid in designing ne therapeutic agents and in providing more rational approaches to treating the consequences of drug abuse.